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WO2009106471A2 - Nouveaux dérivés bloquant les récepteurs de l'angiotensine ii - Google Patents

Nouveaux dérivés bloquant les récepteurs de l'angiotensine ii Download PDF

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WO2009106471A2
WO2009106471A2 PCT/EP2009/051943 EP2009051943W WO2009106471A2 WO 2009106471 A2 WO2009106471 A2 WO 2009106471A2 EP 2009051943 W EP2009051943 W EP 2009051943W WO 2009106471 A2 WO2009106471 A2 WO 2009106471A2
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group
formula
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ono
coo
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WO2009106471A3 (fr
Inventor
Nicoletta Almirante
Alessia Nicotra
Valentino Mandelli
Stefano Biondi
Silvia Stefanini
Iyassu K. Sebhat
Michael Man-Chu Lo
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Nicox SA
Merck and Co Inc
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Nicox SA
Merck and Co Inc
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Priority to US12/866,688 priority Critical patent/US20110052674A1/en
Priority to CA2712695A priority patent/CA2712695A1/fr
Priority to JP2010548079A priority patent/JP2011513269A/ja
Priority to EP09715990A priority patent/EP2250164A2/fr
Publication of WO2009106471A2 publication Critical patent/WO2009106471A2/fr
Publication of WO2009106471A3 publication Critical patent/WO2009106471A3/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to new Angiotensin II Receptor Blocker (ARB) derivatives. More particularly, the present invention relates to new ARB nitroderivatives, pharmaceutical compositions containing them and their use for the treatment of cardiovascular, renal and chronic liver diseases, inflammatory processes and metabolic syndromes .
  • ARB Angiotensin II Receptor Blocker
  • angiotensin II receptor blockers a class of compounds is intended, comprising as main components Losartan, EXP3174, Candesartan, Telmisartan, Valsartan, Eprosartan, Irbesartan and Olmesartan.
  • ARBs are approved for the treatment of hypertension, post-myocardial infarction and heart failure, the antihypertensive activity is due mainly to selective blockade of ATi receptors and the consequent reduced pressor effect of angiotensin II.
  • Angiotensin II stimulates the synthesis and secretion of aldosterone and raises blood pressure via a potent direct vasoconstrictor effect.
  • angiotensin II receptor blockers have side-effects such as for example hypotension, hyperkalaemia, myalgia, respiratory-tract disorders, renal disorders, back pain, gastrointestinal disturbances, fatigue, and neutropenia (Martindale, Thirty-third edition, p. 921) .
  • WO 2005/011646 describes angiotensin II receptor blocker nitroderivatives, pharmaceutical compositions containing them and their use for the treatment of cardiovascular, renal and chronic liver diseases, inflammatory processes and metabolic syndromes.
  • the publication describes a variety of angiotensin II receptor blocker compounds each of which are covalently linked to a bivalent radical capable to release nitric oxide. Specific examples include angiotensin II receptor blockers with one or two nitric oxide-releasing moieties directly linked to the angiotensin II receptor blocker compound through esters or carbonates.
  • WO 2005/023182 describes nitrosated and nitrosylated cardiovascular compounds, and compositions comprising at least one nitrosated and nitrosylated cardiovascular compound and optionally at least one nitric oxide donor.
  • the cardiovascular compound which is nitrosated or nitrosylated may be an aldosterone antagonist, an angiotensin II receptor antagonist, a calcium channel blocker, an endothelin antagonist, a hydralazine compound, a neutral endopeptidase inhibitor or a renin inhibitor.
  • the nitric oxide donor may be selected from S- nitrosothiols, nitrites, nitrates, N-oxo-N-nitrosamines, furoxans, and sydnonimines .
  • WO 2006/093864 discloses novel cardiovascular compounds comprising at least one nitric oxide enhancing group, and pharmaceutically acceptable salts thereof.
  • the cardiovascular compounds can be, for example, aldosterone antagonists, angiotensin II antagonists, endothelin antagonists, hydralazine compounds, neutral endopeptidase inhibitors and renin inhibitors.
  • the nitric oxide enhancing groups are nitroxides and/or heterocyclic nitric oxide donor groups such as furoxans, sydnonimines, oxatriazole-5- ones and/or oxatriazole-5-imines .
  • WO 2007/019448 describes novel nitric oxide enhancing angiotensin II antagonist compounds comprising at least one nitric oxide enhancing group directly or indirectly linked to the angiotensin II antagonist compound through one or more sites such as carbon, oxygen and/or nitrogen via a bond or moiety that cannot be hydrolyzed.
  • the Applicant has surprisingly and unexpectedly found a specific class of nitric oxide-releasing ARBs with good pharmacological profile and oral bioavailability, associated with prolonged duration of action.
  • the angiotensin II receptor blocker nitroderivatives of the present invention exhibit a strong anti-inflammatory, antithrombotic and antiplatelet activity and can be furthermore employed for treating or preventing hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, liver fibrosis, portal hypertension, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra-ocular pressure, atherosclerosis, restenosis post-angioplasty, complications following vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders, complications of treatments with immunosuppressive agents, metabolic syndromes and other diseases known to be related to the renin-an
  • Object of the present invention are, therefore, new angiotensin II receptor blocker nitroderivatives of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof:
  • a and A' are independently selected from the group consisting of -(Y-ONO2), -(Y'-ONO2) or (Ia)
  • R is selected from the following residues of formula (II ' or (III) :
  • R 0 is the group or N 0 which is a moiety capable to bind the groups A and A' as defined hereinafter; Ri is selected from the groups (Va-Ve]
  • R2 is C1-C5 linear or branched alkyl, preferably n- propyl or n-butyl;
  • R3 is an halogen atom such as Cl, Br, I, or a perfluorurated Ci-C 4 alkyl chain, preferably C 2 F 5 , or the group -C(CH 3 ) 2 OH;
  • R 4 is n-Bu or -OEt
  • N 0 is a moiety capable to bind the groups A and A' , having one of the following meanings:
  • K' is equal to -COO-, -CONH-, -CH 2 -O-CO-, -CH 2 -O- COO- or -CH 2 -O-CONH- and K' is bound to the group A wherein A is -(Y-ONO 2 ) or (Ia), with the proviso that when A is (Ia), then K' is -COO- or -CH 2 -OCOO-;
  • J is selected among (VIIa-VIIk) :
  • K' is equal to -COO-, -CONH-, -CH 2 -O-CO-, -CH 2 -O- COO- or -CH 2 -O-CONH- and K' is bound to the group A wherein A is -(Y-ONO 2 ) or (Ia), with the proviso that when A is (Ia), then K' is -COO- or -CH 2 -OCOO-;
  • Ki is selected among (VIIIa-VIIId) :
  • R 5 is H or a group selected from -CO-, -COO- or CONH- capable to bind a group A' wherein A' is - (Y' -ONO 2 ); K 2 is selected among (VIIIe-VIIIf) :
  • R 6 is -OH or a group selected from -0- or -NH capable to bind a group A' , with the proviso that when A' is (Ia), then R 6 is -0-; K 3 is selected among (VIIIg-VIIIh) :
  • R 7 and Rs are H or a group selected from -CO- or - COO- capable to bind a group A' wherein A' is -(Y' -ONO 2 ); K* is equal to K' as above defined or -COOH and when K* is equal to K' is bound to the group A, with the proviso that when A is (Ia), then K' is -COO- or -CH 2 -OCOO-; 4)
  • N 0 is selected from the group consisting of (VIb) , (VIc) -CO-NH-J-K' , -CH 2 -O-CO-NH-J-K', -CO-NH-K-K*, -CH 2 -O-CO-NH-K-K*, (IXc) and (IXa) ; ii) when Ri is selected from the groups (Vb) , (Vc) or (Ve) , then N 0 is selected from the group consisting of (VIb), -CO-NH-J-K', -CO-NH-K-K* and (IXc); iii) when Ri is the group (Vd) , then N 0 is selected from the group consisting of (Via) , -OCO-NH-J-K' , -0-C0- NH-K-K* and (IXb) ; iv
  • Ri is the group (V e ) vi) when R is selected from the residue (II), then s is 1 and s' is 0 or 1 ; vii) when R is selected from the residue (III), then s is 2 and s' is 0 or 2.
  • Y and Y' independently are bivalent radicals having the following meaning: a)
  • n is an integer from 0 to 20, and n 1 is an integer from 1 to 20; d) wherein : n 1 is as defined above and n 2 is an integer from 0 to 2 ;
  • Xi -OCO- or -COO- and R 2 is H or CH 3 ; e
  • n 1 , n 2 ,R 2 and Xi are as defined above;
  • X 2 is -0- or -S-
  • n 3 is an integer from 1 to 6, preferably from 1 to 4, R 2 is as defined above, R 3 is H or -ONO 2 and n 4 is 0 or 1.
  • Ci-C 2 O alkylene refers to branched or straight chain Ci-C 2 O hydrocarbon, preferably having from 1 to 10 carbon atoms such as methylene, ethylene, propylene, isopropylene, n-butylene, pentylene, n-hexylene and the like.
  • Ci-Cio alkyl refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, octyl and the like.
  • Another aspect of the present invention provides the use of the compounds of formula (I) in combination with at least a compound used to treat cardiovascular disease selected from the group consisting of: aldosterone antagonists, renin inhibitors, ACE inhibitors, HMGCoA reductase inhibitors, beta-adrenergic blockers, alpha- adrenergic antagonists, sympatholytics, calcium channel blockers, endothelin antagonists, neutral endopeptidase inhibitors, potassium activators, diuretics, vasodilators, antithrombotics such as aspirin. Also it is contemplated the combination with nitrosated compounds of the above reported compounds .
  • Suitable aldosterone antagonists, renin inhibitors, ACE inhibitors, HMGCoA reductase inhibitors, beta- adrenergic blockers, alpha-adrenergic antagonists, sympatholytics, calcium channel blockers, endothelin antagonists, neutral endopeptidase inhibitors, potassium activators, diuretics, vasodilators and antithrombotics are described in the literature such as The Merck Index (13 th edition) .
  • Suitable nitrosated compounds are disclosed in WO 98/21193, WO 97/16405, WO 98/09948, WO 2004/105754, WO 2004/106300, WO 2004/110432, WO 2005/011646, WO 2005/053685, WO 2005/054218, WO 2007/045551.
  • the administration of the compounds above reported can be carried out simultaneously or successively.
  • the present invention also provides pharmaceutical kits comprising one or more containers filled with one or more of the compounds and/or compositions of the present invention and one or more of the compounds used to treat cardiovascular diseases reported above.
  • the invention includes also the pharmaceutically acceptable salts of the compounds of formula (I) and stereoisomers thereof.
  • Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases, such as lysine, arginine, triethylamine, dibenzylamine, piperidine and other acceptable organic amines .
  • the compounds according to the present invention when they contain in the molecule one salifiable nitrogen atom, can be transformed into the corresponding salts by reaction in an organic solvent such as acetonitrile, tetrahydrofuran with the corresponding organic or inorganic acids.
  • organic acids examples include oxalic, tartaric, maleic, succinic, citric acids.
  • inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acids. Salts with nitric acid are preferred.
  • the compounds of the invention which have one or more asymmetric carbon atoms can exist as optically pure enantiomers, pure diastereomers, enantiomers mixtures, diastereomers mixtures, enantiomer racemic mixtures, racemates or racemate mixtures.
  • optically pure enantiomers pure diastereomers, enantiomers mixtures, diastereomers mixtures, enantiomer racemic mixtures, racemates or racemate mixtures.
  • isomers, stereoisomers and their mixtures of the compounds of formula (I) are also all the possible isomers, stereoisomers and their mixtures of the compounds of formula (I) .
  • R is the residue of formula (II) wherein R 0 is the group of formula (IV), Ri is the group of formula (Va), R2 is n-butyl, R3 is Cl and all other variables are as above defined.
  • R is the residue of formula (II) wherein Ro is the group of formula (IV), Ri is the group of formula (Va) , R2 is n-propyl, R3 is the group - C(CH 3 ) 2 OH and all other variables are as above defined.
  • R is the residue of formula (II) wherein Ro is the group of formula (IV) as defined above, Ri is the group of formula (Vc) as defined above, R 4 is -OEt, and all other variables are as above defined.
  • Si is 0 and A is the group (VI a ) or (VI b ) or (VI C ) as defined above wherein K' is -COO-, and all other variables are as above defined.
  • Si is 0 and A is -CO-NH-J-K' or -CH 2 - O-CO-NH-J-K' wherein J is the group (Vila) or (VIIb) as defined above, wherein K' is -COO-, and all other variables are as above defined.
  • Si is 0 and A is -CH 2 -O-CO-NH-K-K* or -CO-NH-K-K* wherein K is K 3 which is the group (VIIIg) or (VIIIh) as defined above, and all other variables are as above defined.
  • Y and Y' independently are bivalent radicals having the following meaning: a) - straight or branched C1-C10 alkylene, being optionally substituted with one or more -ONO 2 ; b)
  • n is an integer from 0 to 5
  • n 1 is an integer from 1 to 5; with the proviso that when Y or Y' is selected from the bivalent radical b) , the -ONO2 group is linked to a -(CH 2 ),! 1 group; f)
  • X 2 is -O- or -S-, n 3 is 1, R 2 is H, R 3 is H or -ONO 2 and n 4 is 0 or 1.
  • object of the present invention are also pharmaceutical compositions containing at least a compound of the present invention of formula (I) together with non toxic adiuvants and/or carriers usually employed in the pharmaceutical field.
  • the daily dose of active ingredient that should be administered can be a single dose or it can be an effective amount divided into several smaller doses that are to be administered throughout the day. Usually, total daily dose may be in amounts preferably from 50 to 500 mg.
  • the dosage regimen and administration frequency for treating the mentioned diseases with the compound of the invention and/or with the pharmaceutical compositions of the present invention will be selected in accordance with a variety of factors, including for example age, body weight, sex and medical condition of the patient as well as severity of the disease, route of administration, pharmacological considerations and eventual concomitant therapy with other drugs. In some instances, dosage levels below or above the aforesaid range and/or more frequent may be adequate, and this logically will be within the judgment of the physician and will depend on the disease state.
  • the compounds of the invention may be administered orally, parenterally, rectally or topically, by inhalation or aerosol, in formulations eventually containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • transdermal administration such as transdermal patches or iontophoresis devices.
  • parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • injectable preparations for example sterile injectable aqueous or oleaginous suspensions may be formulated according to known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • acceptable vehicles and solvents are water, Ringer's solution and isotonic sodium chloride.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono or diglycerides, in addition fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the active ingredient with a suitable non-irritating excipient, such as cocoa butter and polyethylene glycols.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, granules and gels.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g. lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavouring and the like.
  • the compounds of the present invention can be synthesized as follows.
  • A is - (Y-ONO2) wherein Y is as above defined;
  • R is selected from the residue of formula (II) wherein R 0 is (IV) and Ri is selected from the group (Va) wherein:
  • R 2 is n-butyl and R 3 is Cl, and N 0 is selected from:
  • R a is selected from the residue of formula (II) wherein Ri, R 2 , R 3 and N 0 are as above defined in 1.;
  • Ro is equal to (IVa) and is equal to: with anhydrous or aqueous organic or inorganic acid to hydrolyze the trityl protective group following procedure well known in the literature; alternatively the trityl protective group can be removed treating with an alcoholic solvent such is metanol or ethanol at temperature from 20- 100° C for 1-48 hrs;
  • A is -(Y-ONO 2 ) wherein Y is as above defined;
  • A is - (Y-ONO 2 ) , Y and J are as above defined; in the presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH 2 Cl 2 at temperatures range between 0°-100°C for time range of 1- 60 hrs, or under microwave irradiation in the presence of DMAP and a Lewis acid such as Sc(OTf) 3 or Bi(OTf) 3 in solvents such as DMF, CH 2 Cl 2 at temperatures range between 60°-120°C for time range of 1-120 min, ;
  • Compound R ⁇ a is Losartan and compound R ⁇ a - is trityl losartan: both compounds are known and commercially available.
  • R IIa the deprotection step described in Ia) is required.
  • A is - (Y-ONO2) wherein Y is as above defined;
  • R is selected from the residue of formula (II) wherein R 0 is (IV) and Ri is selected from the group (Vd) and N 0 is selected from: 1) (Via), wherein K' is equal to -COO-, -CONH-, -CH 2 -O-CO-,
  • K' is as above defined; can be prepared as follows
  • R b is selected from the residue of formula (II) wherein Ri and N 0 are as above defined in 2.; Ro is equal to (IVb) and is equal to:
  • A is - (Y-ONO2) wherein Y is as above defined,
  • R is selected from the residue of formula (II) wherein R 0 is (IV), Ri is selected from the group: i) (Va) wherein R 2 is n-butyl and R3 is Cl; ii) (Va) wherein R 2 is n-propyl and R3 is C 2 F 5 ,- iii) (Va) wherein R 2 is n-propyl and R3 is the group
  • N 0 is selected from:
  • R c is selected from the residue of formula (II) wherein N 0 is as above defined in 3. and Ri is as above defined in the points i)- vi) ; R 0 is equal to (IVa) and is as previously defined, following the same procedure described in Ia) ; 3b) by reacting : i) a compound of formula R llc
  • N 00 is -COOH, -COHaI or -COOAct wherein Hal is an halogen atom such as Cl, Br, F; Act is a carboxylic acid activating group used in peptide chemistry such as:
  • N O o is as previously defined; or iii) a compound of formula R ⁇ e
  • N O o is as previously defined; or vi) a compound of formula R ⁇ h
  • N O o is as previously defined; with 3b.1) a compound of formula (Xc a ) - (Xc e ) depending on the meaning of K'
  • A is -(Y-ONO 2 )
  • N 00 -COOH: a condensing agent such as dicyclohexylcarbodiimide (DCC) or N, N' -carbonyldiimidazol (CDI) or other known condensing reagents such as 0- (7-azabenzotriazol-l-yl) -N, N, N ' , N ' - tetramethyluronium hexafluorophosphate (HATU) , in the presence or not of 1-Hydroxybenzotriazole (HOBT) in solvent such as DMF, THF, chloroform at a temperature in the range from -5°C to 80 0 C in the presence or not of a base as for example DMAP.
  • DCC dicyclohexylcarbodiimide
  • CDI N, N' -carbonyldiimidazol
  • HATU 1-Hydroxybenzotriazole
  • solvent such as DMF, THF, chloroform at
  • N 00 -COHaI or -COOAct: the reaction is generally carried out in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH 2 Cl 2 at temperatures range between 0°-80°C or in a double phase system H 2 0/Et 2 0 at temperatures range between 20°-40°C; or in the presence of
  • the reaction is generally carried out in presence of a base in an aprotic polar/non-polar solvent such as DMF, THF or CH2CI2 at temperatures range between -15°-+80°C or in a double phase system H 2 O/Et2 ⁇ at temperatures range between 20°- 40 0 C.
  • an aprotic polar/non-polar solvent such as DMF, THF or CH2CI2 at temperatures range between -15°-+80°C or in a double phase system H 2 O/Et2 ⁇ at temperatures range between 20°- 40 0 C.
  • Compound C can be prepared by KMnO 4 oxidation as described in WO 2005/011646 of the corresponding aldehyde D, commercially available:
  • Ru e wherein -N O o is -COOH can be prepared from compound R ⁇ ( known as EXP 3174:
  • Rii d wherein -N O o is -COOH is known as trityl DuP 532 and can be prepared as described by Michael E. Pierce in J. Org.
  • Ru e wherein -N O o is -COOH is known as trityl olmesartan and is commercially available;
  • Rii f wherein -N O o is -COOH is known as trityl valsartan and is commercially available Rug wherein -N O o is -COOH can be prepared from compound Rn gg known as CV 11194 by reacting with trityl chloride as already described for R llcc ;
  • Riigg can be prepared as decribed by Kubo, K. et al, in J.
  • Riih wherein -Noo is -COOH is known as trityl candesartan and is commercially available.
  • A is - (Y-ONO2) wherein Y is as above defined,
  • Compound Rn 1 is known as telmisartan and is commercially available :
  • Compound Rm a is known as eprosartan and is commercially available :
  • A is - (Y-ONO2) wherein Y is as above defined,
  • R is selected from the residue of formula (II) wherein R 0 is (IV) and Ri is selected from the group (Va) wherein:
  • R2 is n-butyl
  • R3 is Cl
  • N 0 is selected from: 1) -CH 2 -O-CO-NH-K-K* wherein K* is equal to K' and is equal to -COO-, -CONH-, -CH 2 -O-CO-, -CH 2 -O-COO- or -CH 2 -O-CONH- and K* is bound to the group - (Y-ONO 2 )
  • K is selected from Ki, K 2 or K 3 and is selected from (VIIIa)-(VIIIh) wherein R 5 , R 7 and R 8 are -H, R 6 is -OH 2)
  • IXa wherein K* is equal to K' and is as above defined and R 7 is -H
  • R d is selected from the residue of formula (II) wherein Ri, R 2 and R3 are as above defined in 5.; Ro is equal to (IVa) and is as defined in Ia); N 0 is equal to N Oa and is equal to:
  • K a is selected from (Vlllaa) - (Vlllha) (see Appendix 1, preparation A7) ; or 5a.2)
  • No a is the group IXa a wherein K* and Boc are as previously defined; with anhydrous or aqueous organic or inorganic acid to hydrolyze the trityl and the other protective groups following procedure well known in the literature; 5b) by reacting a compound of formula R ⁇ a' above described:
  • A is - (Y-ONO 2 )
  • A is - (Y-ONO2) wherein Y is as above defined, R is selected from the residue of formula (II) wherein R 0 is (IV) and Ri is selected from the group (Vd) and No is selected from: 1) -O-CO-NH-K-K* wherein K* is equal to K' and is equal to -COO-, -CONH-, -CH 2 -O-CO-, -CH 2 -O-COO- or -CH 2 -O-CONH- and K* is bound to the group - (Y-ONO 2 ) ; K is selected from (VIIIa)-(VIIIh) wherein R 5 , R 7 and R 8 are -H, R 6 is -OH 2) (IXb) wherein K* is as above defined and R 7 is -H; can be prepared as follows
  • R e is selected from the residue of formula (II) wherein Ri and No are as above defined in 6.; Ro is equal to (IVb) and is the t- butyl protecting group as defined in 2a) ; N 0 is equal to N Ob and is equal to: 6a.1) -0-CO-NH-K a -K* wherein K* is as above defined in 6.
  • K* is bound to the group - (Y-ONO 2 ) ;
  • K a is selected from (Vlllaa) - (Vlllha) as already described in 5a); or 6a.2)
  • No b is the group IXb a : wherein K* and Boc are as previously defined; with anhydrous or aqueous organic or inorganic acid to hydrolyze the t-butyl and the other protective groups following procedure well known in the literature; 6b) by reacting a compound of formula Ru b :
  • A is - (Y-ONO2) wherein Y is as above defined, R is selected from the residue of formula (II) wherein Ro is (IV), Ri is selected from the group: i) (Va) wherein R2 is n-butyl and R3 is Cl; ii) (Va) wherein R 2 is n-propyl and R3 is C 2 F 5 , iii) (Va) wherein R 2 is n-propyl and R3 is the group
  • No is selected from: 1) -CO-NH-K-K* wherein K* is equal to K' and is equal to - COO-, -CONH-, -CH 2 -O-CO-, -CH 2 -O-COO- or -CH 2 -O-CONH- and K* is bound to the group - (Y-ONO 2 ) ;
  • K is selected from (VIIIa)-(VIIIh) wherein R 5 , R 7 and R 8 are -H, R 6 is -OH; 2) (IXc) wherein K* is as above defined and R 7 is -H; can be prepared as follows:
  • R f is selected from the residue of formula (II) wherein Ri is as above defined in 7. in the points i)-vi); R 0 is equal to (IVa) and is as previously defined, N 0 is equal to N Oc and is equal to:
  • K* is as above defined in 7. and K* is bound to the group - (Y-ONO 2 ) ; K a is as defined in
  • A is - (Y-ONO2) and Y is as above defined; following the procedures reported in 3c) for:
  • N 00 -COHaI or -COOAct:
  • A is - (Y-ONO2) wherein Y is as above defined,
  • K* is as above defined and is equal to -C00-, -CONH-, -CH 2 -O-CO-, -CH 2 -O-COO- or -CH 2 -O-CONH- and K* is bound to the group - (Y-ONO 2 ) ;
  • K is selected from (VIIIa)-(VIIIh) wherein R 5 , R 7 and R 8 are -H, R 6 is -OH; 2) (IXc) wherein K* is as above defined and R 7 is -H; can be prepared as follows:
  • a and A' are -(Y-ONO 2 ) or -(Y' -ONO 2 ) wherein Y and Y' are equal or different and are as above defined, R is selected from the residue of formula (II) wherein Ro is (IV) and Ri is selected from the group (Va) wherein: R 2 is n-butyl, R3 is Cl, and N 0 is selected from: 1) -CH 2 -O-CO-NH-K-K* wherein K* is equal to K' is equal to -COO-, -CONH-, -CH 2 -O-CO-, -CH 2 -O-COO- or -CH 2 -O-CONH- and K* is bound to the group -(Y-ONO 2 ); K is selected from Ki, K 2 or K 3 and is selected from (VIIIa)-(VIIIh) wherein R 5 is selected from -CO-, -COO- or -CONH-; R 6 is selected from -
  • R 7 and R 8 are selected from -CO- or -COO- and K is bound to the group - (Y' -ONO 2 );
  • R g is selected from the residue of formula (II) wherein Ri, R 2 and
  • R3 are as above defined in 9.; Ro is equal to (IVa) and is as defined in Ia); N 0 is equal to:
  • K* is equal to -COO-, -CONH-, -CH 2 -O-CO-, -CH 2 -O-
  • R 7 is selected from -CO- or -COO- and R 7 is bound to the group -(Y' -ONO 2 ) . following the procedure described in Ib) ;
  • a and A' are -(Y-ONO 2 ) or -(Y' -ONO 2 ) wherein Y and Y' are equal or different and are as above defined,
  • R is selected from the residue of formula (II) wherein Ro is (IV) and Ri is selected from the group (Vd) and N 0 is selected from: 1) -0-CO-NH-K-K* wherein K* is equal to K' and is equal to -COO-, -CONH-, -CH 2 -O-CO-, -CH 2 -O-COO- or -CH 2 -O-CONH- and K* is bound to the group - (Y-ONO 2 ) ; K is selected from Ki, K 2 or K 3 and is selected from (VIIIa)-(VIIIh) wherein R 5 is selected from -CO-, -COO- or -CONH-; R 6 is selected from - 0- or -NH; R 7 and R 8 are selected from -CO- or -COO- and K is bound to the group - (Y' -ONO 2 );
  • R h is selected from the residue of formula (II) wherein Ri and No are as above defined in 10.; Ro is equal to (IVb) and is the t-butyl protecting group as defined in 2a) ; N 0 is equal to: 10a.1) -0-CO-NH-K-K* wherein K is selected from K x , K 2 or K 3 and K and K* are as above defined in 10.; Ki, K 2 , K 3 and K* are respectively bound to the group -(Y' -ONO 2 ) and -(Y- ONO 2 ) ; 10a.2) (IXb) wherein K* and R 7 are as above defined in 10.; R 7 is bound to the group - (Y' -ONO 2 ); with anhydrous or aqueous organic or inorganic acid to hydrolyze the t-butyl group following procedure well known in the literature; 10b) by reacting a compound of formula Ru
  • a and A' are -(Y-ONO 2 ) or -(Y' -ONO 2 ) wherein Y and Y' are as above defined, R is selected from the residue of formula (II) wherein R 0 is (IV), Ri is selected from the group: i) (Va) wherein R 2 is n-butyl and R3 is Cl; ii) (Va) wherein R 2 is n-propyl and R3 is C 2 F 5 , i i i ) (Va ) wherein R 2 i s n-propyl and R3 i s the group -
  • K* is equal to K' and is equal to - COO-, -CONH-, -CH 2 -O-CO-, -CH 2 -O-COO- or -CH 2 -O-CONH- and K* is bound to the group - (Y-ONO 2 )
  • K is selected from Ki, K 2 or K 3 and is selected from (VIIIa)-(VIIIh) wherein R 5 is selected from -CO-, -COO- or -CONH-; R 6 is selected from - 0- or -NH; R 7 and R 8 are selected from -CO- or -COO- and K is bound to the group - (Y' -ONO 2 );
  • R 1 is selected from the residue of formula (II) wherein No is as above defined, Ri is as above defined in 11. in the points i)-vi); R 0 is equal to (IVa) and is as previously defined, with anhydrous or aqueous organic or inorganic acid to hydrolyze the trityl and the other protective groups following procedure well known in the literature; lib) by reacting compounds of formula R ⁇ c - R IIh already defined in 3b) with llb.l) compounds of general formula (Xk a ) - (Xk 0 ) NH 2 -K-K*
  • R 7 is selected from -CO- or -COO- and R 7 is bound to the group -(Y' -ONO 2 ); following the procedures reported in 3c) for:
  • N 00 -COHaI or -COOAct:
  • R is selected from the residue of formula (II) wherein R 0 is (IV) and Ri is selected from the group (Va) wherein: R2 is n-butyl, R3 is Cl, and N 0 is selected from:
  • K is selected from Ki, K 2 or K 3 and is selected from (VIIIa)-
  • R 1 is selected from the residue of formula (II) wherein Ri, R 2 and R 3 are as above defined in 13.; Ro is equal to (IVa) and is as defined in Ia); N 0 is equal to N Oa and is equal to: 13a.1) -CH 2 -O-CO-NH-K-K x * wherein K x * is equal to -COOt-But;
  • K is selected from Ki, K 2 or K 3 and is selected from
  • t-But is the tert-butyl protecting group and R 7 is selected from -CO- or -COO- and binds the group - (Y' -ONO 2 ); with anhydrous or aqueous organic or inorganic acid to hydrolyze the trityl and the other protective groups following procedure well known in the literature;
  • Ki is selected from (VIIIa)-(VIIId) wherein R 5 is selected from respectively: i) -CO- (Xi a4 ); ii) -COO- (Xi a5 ) ; or iii) -CONH- (Xi a6 ) ; and Ki is bound to the group -(Y'-ON ⁇ 2) (see Appendix 1, preparation A9/2) ;
  • K 3 is selected from (VIIIh) , (VIIIg) wherein R 7 and Rs are selected from respectively: i) -CO- (Xi k3 ) or ii) -COO- (Xi k4 ) and K 3 is bound to the group -(Y' -ONO 2 ) (see Appendix 1, preparation A19/2) ;
  • R 7 is selected from respectively: i) "CO- (Xja3), ii) -COO- (Xja4) and R 7 is bound to the group -(Y' -ONO 2 ) (see Appendix 1, preparation A24/2) ; following the procedure described in Ib) . 14.
  • the compounds of general formula (I) are selected from respectively: i) "CO- (Xja3), ii) -COO- (Xja4) and R 7 is bound to the group -(Y' -ONO 2 ) (see Appendix 1, preparation A24/2) ; following the procedure described in Ib) . 14.
  • A' is -(Y'-ON ⁇ 2 ) wherein Y' is as above defined;
  • R is selected from the residue of formula (II) wherein R 0 is (IV) and Ri is selected from the group (Vd) and N 0 is selected from: 1) -O-CO-NH-K-K* wherein K* is equal to -COOH; K is selected from Ki, K 2 or K 3 and is selected from (VIIIa)-
  • R 5 is selected from -CO-, -COO- or -CONH-;
  • Re is selected from -0- or -NH; R 7 and Rs are selected from
  • K is bound to the group - (Y' -ONO 2 ); 2) (IXb) wherein K* is equal to -COOH and R 7 is -CO- or -
  • COO- and R 7 is bound to the group - (Y' -ONO 2 ); can be prepared as follows:
  • R k is selected from the residue of formula (II) wherein Ri is as above defined in 14.; R 0 is equal to (IVb) and is as defined in 2a); N 0 is equal to N O b and is equal to: 14a.1) -0-CO-NH-K-K x * wherein K x * is equal to -COOt-But; K is selected from Ki, K 2 or K 3 and is selected from (VIIIa)- (VIIIh) wherein R 5 is selected from -CO-, -COO- or -CONH-; Re is selected from -0- or -NH; R 7 and Rs are selected from -CO- or -COO- and K is bound to the group - (Y' -ONO 2 ); or 14a.2) Nob is the group IXb b
  • t-But is the tert-butyl protecting group and R 7 is selected from -CO- or -COO- and binds the group - (Y' -ONO 2 ); with anhydrous or aqueous organic or inorganic acid to hydrolyze the trityl and the other protective groups following procedure well known in the literature;
  • R is selected from the residue of formula (II) wherein R 0 is (IV), Ri is selected from the group: i) (Va) wherein R 2 is n-butyl and R3 is Cl; ii) (Va) wherein R 2 is n-propyl and R3 is C 2 F 5 , iii) (Va) wherein R 2 is n-propyl and R3 is the group -
  • N 0 is selected from:
  • K is selected from K 1 , K 2 or K 3 and is selected from (VIIIa)-(VIIIh) wherein R 5 is selected from -CO-, -COO- or -CONH-; R 6 is selected from -0- or -NH; R 7 and Rs are selected from -CO- or -COO- and K is bound to the group - (Y' -ONO 2 );
  • R L is selected from the residue of formula (II) wherein Ri is as above defined in 15. in the points i)-vi); Ro is equal to
  • N 0 is equal to N Oc and is equal to:
  • K x * is equal to -COOt-But; K is as defined in 15.;
  • Noc is the group IXc b : wherein R 7 and t-But are as previously defined; with anhydrous or aqueous organic or inorganic acid to hydrolyze the trityl and the other protective groups following procedure well known in the literature; 15b) by reacting compounds of formula R ⁇ c - R IIh already defined in 3b), depending on the meaning of K with: 15b.1) compounds of formula (Xk a4 ) - (Xk a6 ) :
  • Ki is selected from (VIIIa)-(VIIId) wherein R 5 is selected from respectively: i) -CO- (Xk a4 ); ii) -COO- (Xk a5 ) ; or iii) -CONH- (Xk a6 ) ; and Ki is bound to the group -(Y' -ONO 2 ) (see Appendix 1, preparation A9/2) ; or
  • K 2 is selected from: i) -0- (Xk f3 ) or ii) -NH- (Xk f4 ) and K 2 is bound to the group -(Y' -ONO 2 I [see Appendix 1, preparation A14/2) ; or
  • K 3 is selected from (VIIIh) , (VIIIg) wherein R 7 and Rs are selected from respectively: i) -CO- (Xk k3 ) or ii) -COO- (Xk k4 ) and K 3 is bound to the group -(Y' -ONO 2 ) (see Appendix 1, preparation A19/2) ; or 15b.4) compounds of formula (XL a3 ) , (XL a4 ) :
  • N 00 -COHaI or -COOAct.
  • s is equal to 0 ; s ' i s equal to 1 or 2 ;
  • K is selected from K 1 , K 2 or K 3 and is selected from (VIIIa)-(VIIIh) wherein R 5 is selected from -CO-, -COO- or -CONH-; R 6 is selected from -0- or -NH; R 7 and Rs are selected from -CO- or -COO- and K is bound to the group - (Y' -ONO 2 );
  • R is selected from the residue of formula (II) wherein Ro is (IV), Ri is selected from the group: i) (Va) wherein R2 is n-butyl and R3 is Cl; iii) (Va) wherein R 2 is n-propyl and R3 is the group
  • N 00 is -COOH, -COHaI or -COOAct wherein Hal and Act are as previously defined in 3.; or iii) a compound of formula R ⁇ e
  • N O o is as previously defined
  • A is the group (Ia),
  • XIa dicyclohexylcarbodiimide
  • CDI N, N' -carbonyldiimidazol
  • EDC l-ethyl-3- (3 ' - dimethylaminopropyl) carbodiimide hydrochloride
  • other known condensing reagents such as O- (7- azabenzotriazol-1-yl) -N, N,N',N r -tetramethyluronium hexafluorophosphate (HATU) , in the presence or not of 1- Hydroxybenzotriazole (HOBT) in solvent such as CH 2 Cl 2 , DMF, THF, chloroform at a temperature in the range from -5°C to 80 °C in the presence or not of a base as for example DMAP. 17c) by reacting compound R ⁇ c defined in 3b)
  • J is as previously defined using a condensing agent as l-ethyl-3- (3 ' -dimethylaminopropyl) carbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole as known in the literature and hydrolysing the final methyl ester with NaOH in solvent such as MeOH as well known in the literature .
  • EDC carbodiimide hydrochloride
  • 1-hydroxybenzotriazole as known in the literature and hydrolysing the final methyl ester with NaOH in solvent such as MeOH as well known in the literature .
  • Compounds of formula (XIa) wherein A is the group (Ia) are commercially available.
  • Compounds of formula (XIa) wherein A is the group - (Y-ONO2) are obtained by reacting compounds of formula HO-Y-HaI (XIIa) wherein Y is as above defined and Hal is an halogen atom such as Cl, Br, I or compounds of formula HO-Y-OTs (XIIIa) wherein Ts is the tosyl group, with AgN ⁇ 3 or MetalN ⁇ 3 wherein Metal is K + , Na + Li + in a suitable organic solvent such as acetonitrile or tetrahydrofuran (THF) under nitrogen in the dark at temperatures range between 20°-80°C using a nitrate ammonium salt as catalyst; alternatively the reaction with AgN ⁇ 3 or MetalN ⁇ 3 can be performed under microwave irradiation in solvents such acetonitrile or THF at temperatures in the range between about 100-180 0 C for
  • the compounds of formula (XIb) are obtained by reacting compounds of formula BocNH-Y-Hal (XIIb) wherein Y and Hal are as above defined or compounds of formula BocNH-Y-OTs (XIVa) wherein Ts is the tosyl group, with AgN ⁇ 3 or MetalN ⁇ 3 as already described in Al, eventually acid hydrolysing the Boc protective group.
  • the compounds of formula (XIIb) and (XIVa) are commercially available or can be obtained from commercially available compounds BocNH-Y- OH (XIVb) with methods well known in the literature. A3. Synthesis of compounds (Xa c ) and (Xc c )
  • K a is selected from (VHIaa) - (Vlllha) :
  • Trt is the trityl protecting group
  • t-But is the t- Butyl protecting group
  • Boc is the Boc protecting group
  • Pfb is the (2, 2, 4, 6, 7-pentamethyl-dihydrobenzofuran-5- sulfonyl)- protecting group; are obtained by reaction with pNO 2 -C 6 H 4 -OCOCl of the corresponding compounds (Xg a ) - (Xg e ) :
  • Ki is selected from (VIIIa)-(VIIId) wherein R 5 is selected from respectively: i) -CO- (Xi a4 ); ii) -COO- (Xi a5 ) ; or iii) -CONH- (Xi a6 ) ; and Ki is bound to the group - (Y ' -ONO 2 ) are obtained by reaction with pNO 2 -C 6 H 4 -OCOCl of the corresponding compounds (Xk a4 ) - (Xk a6 ) :
  • Ki is selected from (VIIIa)-(VIIId) wherein R 5 is selected from respectively: i) -CO- (Xk a4 ); ii) -COO- (Xk a5 ) ; or i i i ) -CONH- (Xk a6 ) ;
  • R 6 is selected from respectively: i) -0- (Xifi) or ii) -NH- (Xi f2 ) and K 2 is bound to the group -(Y' -ONO 2 ) are obtained by reaction with pNO 2 -C6H 4 -OCOCl of the corresponding compounds
  • K 2 is selected from (VIIIe), (VIIIf) wherein R 6 is selected from respectively: i) -0- (Xigi) or ii) -NH- (XI g2 ) and K 2 is bound to the group -(Y' -ONO 2 ) are obtained by reaction with pNO 2 -C6H 4 -OCOCl of the corresponding compounds (Xkgl), (Xkg 2 )
  • K 2 is selected from: i) -0- (Xkgi) or ii) -NH- (Xk g2 )
  • K 3 is selected from (VIIIh) , (VIIIg) wherein R 7 and Rs are selected from respectively: i) -CO- (Xk k3 ) or ii) -COO- (Xk k4 ) and K 3 is bound to the group -(Y' -ONO 2 )
  • R 7 is selected from respectively: i) -CO- (Xjal), (Xjbl), (Xjd), (Xjdl), (Xjel); ii) -COO- (Xj a2 ), (XJb 2 ), (XJc 2 ), (XJd 2 ), (XJe 2 ); and R 7 is bound to the group -(Y'-ON ⁇ 2) are obtained by reaction with pNO 2 -C 6 H 4 -OCOCl of the corresponding compounds (XL a i), (XLa 2 ); (XL bl ) -(XLb 2 ); (XLci) -(XL c2 ); (XL dl ) - (XL d2 ) ; (XLei)-(XL e2 ) :
  • the compounds (XlXai) - (XIXa 5 ) can be obtained by acid hydrolyzing the Boc protective group of compounds (Xh a ) -
  • R 7 is selected from respectively: i) -CO- (XJa 3 ), ii) -COO- (Xja4) and R 7 is bound to the group -(Y' -ONO 2 ) are obtained by reaction with PNO 2 -CeH 4 -OCOCl of the corresponding compounds (XL a 3) , (XL a4 ) :
  • Step B (S) -4- (nitrooxy) butyl 2- ( ( (1- ( (2 ' - (lH-tetrazol-5- yl) biphenyl-4-yl) methyl) -2-butyl-4-chloro-lH-imidazol-5- yl) methoxy) carbonylamino) -6- (tert- butoxycarbonylamino) hexanoate
  • Step A The crude obtained in Step A was dissolved in MeOH (14 ml) and the reaction was heated in a microwave apparatus (90 0 C, 23 min) . Then the mixture was evaporated under reduced pressure and the residue was purified by flash chromatography (DCM/MeOH: 98/2) yielding the title compound.
  • Step C 4- (nitrooxy) butyl 2- ( ( (1- ( (2 ' - (lH-tetrazol-5- yl) biphenyl-4-yl) methyl) -2-butyl-4-chloro-lH-imidazol-5- yl) methoxy) carbonylamino) -6-aminohexanoate
  • Step A 4- (Nitrooxy) butyl 2- (2-butyl-4-chloro-l- ( (2 ' - (1- trityl-lH-tetrazol-5-yl) biphenyl-4-yl) methyl) -lH-imidazole- 5-carboxamido) acetate
  • Step B 4- (Nitrooxybutyl 2- (1- ( (2 ' - (2H-tetrazol-5- yl) biphenyl-4-yl) methyl) -2 -butyl-4 -chloro- IH-imidazole-5- carboxamido) acetate
  • Step A methyl (2S) -2- ⁇ [ ( 2 -butyl-4 -chloro- 1 - ⁇ [2 '- (IH- tetrazol-5-yl) biphenyl-4-yl ] methyl ⁇ -lH-imidazol-5- yl) carbonyl] amino ⁇ -3-phenylpropanoate
  • Step B (2S) -2- ⁇ [ (2-butyl-4-chloro-l- ⁇ [2 ' - (ltf-tetrazol-5- yl) biphenyl-4-yl ] methyl ⁇ -lH-imidazol-5-yl) carbonyl ] amino ⁇ - 3-phenylpropanoic acid
  • Step C (S) - ( (R) -5, 6-bis (nitrooxy) hexyl) 2-(1-((2'-(1H- tetrazol-5-yl) biphenyl-4-yl) methyl) -2-butyl-4-chloro-lH- imidazole-5-carboxamido) -3-phenylpropanoate (2S) -2- ⁇ [ (2-Butyl-4-chloro-l- ⁇ [2'- (lH-tetrazol-5- yl) biphenyl-4-yl] methyl ⁇ -lH-imidazol-5-yl) carbonyl] amino ⁇ - 3-phenylpropanoic acid (0.50 g, 0.86 mmol), (2R) -6- hydroxyhexane-1, 2-diyl dinitrate (0.19 g, 0.86 mmol), 1- ethyl-3- (3 ' -dimethylaminopropyl) car
  • Step A (3S, 3a.R, 6.R, 6aS) -6- (nitrooxy) hexahydrofuro [3, 2- b] furan-3-yl ⁇ [ ( 3H-fluoren-9-ylmethoxy) carbonyl] amino ⁇ acetate
  • Step B (3S, 3a.R, 6R, 6aS) -6- (nitrooxy) hexahydrofuro [3, 2- b] furan-3-yl ⁇ [ (2-butyl-4-chloro-l- ⁇ [2 '- (ltf-tetrazol-5- yl) biphenyl-4-yl] methyl ⁇ -lff-imidazol-5-yl) carbonyl] amino ⁇ acetate
  • N, N-dimethylformamide solution 100 mL
  • Step B 2, 5-dioxopyrrolidin-l-yl 2-butyl-4-chloro-l- ( (2 ' - (2-trityl-2H-tetrazol-5-yl)biphenyl-4-yl) methyl) -IH- imidazole-5-carboxylate
  • Step B 2-aminoethyl 4- (nitrooxy) butanoate hydrochloride Step C j 2- ( (4-nitrophenoxy) carbonylamino) ethyl 4 ⁇
  • Step A 4-hydroxybutyl 2- (tert-butoxycarbonylamino) acetate
  • Step B j 4- (nitrooxy) butyl 2- (tert- butoxycarbonylamino) acetate
  • Step C 4- (nitrooxy) butyl 2-aminoacetate
  • Step Ej 4- (nitrooxy) butyl 2- ( (4- nitrophenoxy) carbonylamino) acetate
  • Step B j (S) -4- (nitrooxy) butyl 2-amino-6- (tert- butoxycarbonylamino) hexanoate
  • IlQoQo organic layer was dried over sodium sulphate and concentrated under reduced pressure.
  • Step C (S) -4- (nitrooxy) butyl 6- (tert-butoxycarbonylamino) -
  • Step A 4- (nitrooxy) butyl 2- (tert- butoxycarbonylamino) acetate
  • the title compound was obtained from N-Boc-L-glycine, N- hydroxysuccinimido ester following procedures described in Intermediate 4, Step A.
  • Step B 4- (nitrooxy) butyl 2-aminoacetate To a solution of 4- (nitrooxy) butyl 2- (tert- butoxycarbonylamino) acetate (3.00 g, 1.03 mmol) in CH2CI2
  • Step A 2-butyl-4-chloro-l- ⁇ [2 ' - (lH-tetrazol-5-yl) biphenyl- 4-yl] methyl ⁇ -IH-imidazole-5-carboxylic acid
  • Water (10 L) was added to a 22 L 4-neck round bottom flask. The water was cooled to 0 0 C. At 0 0 C, potassium hydroxide (855 g, 15.24 mol) was added followed by losartan potassium (500 g, 1.09 mol)), sodium periodate (554 g, 2.59 mol) and ruthenium (III) chloride hydrate (12 g, 0.05 mol) and the reaction mixture was stirred at 0 0 C overnight. The reaction mixture was filtered.
  • IPA (90 mL) was added to the filtrate while stirring. The solution was warmed to 25 0 C and stirred for 2.5 hrs . After 2.5 hrs . , phosphoric acid (1200 mL) was added, maintaining the temperature below +30 0 C. The mixture was stirred for 30 min and the product was filtered, washing with water. The residue was dried in the vacuum oven at 55 0 C overnight. The solid was dissolved in methanol (4 L) and isopropyl acetate (12 L), and charcoal (activated carbon) (100 g) was added. The mixture was stirred at rt for 3.5 hrs, filtered and concentrated. The product was redissolved in DCM/MeOH and precipitated with heptane to afford the title compound as a greenish/brown foam which was used in subsequent steps without further purification.
  • Step B 2-butyl-4-chloro-l- ⁇ [2 ' - (2-trityl-2H-tetrazol-5- yl) biphenyl-4-yl ] methyl ⁇ -IH-imidazole-5-carboxylic acid
  • Step B j tert-butyl 2- (4- (nitrooxy) butylamino) -2- oxoethylcarbamate
  • tert-butyl 2- (4-hydroxybutylamino) -2- oxoethylcarbamate (2.16 g, 8.77 mmol)
  • tetraethylammonium nitrate (3.37 g, 17.54 mmol)
  • 2, 6-di-tert-butyl-4- methylpyridine (2.71 g, 13.16 mmol) in CH2C12 (60 ml) cooled to -70 0 C and under nitrogen
  • a solution of trifluoromethansulfonic anhydride (2.72 g, 9.65 mmol) in CH2C12 (40 ml) was added drop wise.
  • the resulting mixture was stirred for 3 hours at -65°C. Then the mixture was slowly warmed to room temperature, diluted with CH2C12 and washed with 5% aqueous Na2HPO4. The organic layer was dried over sodium sulphate and concentrated under reduced pressure .
  • Step C 4- (2-aminoacetamido) butyl nitrate
  • Step B j 4- [ (nitrooxy) methyl] benzyl 2- (tert- butoxycarbonylamino) acetate To a solution of 4- (chloromethyl) benzyl 2- (tert- butoxycarbonylamino) acetate ester (0.605 g, 1.78 mmol) in
  • Step C 4- [ (nitrooxy) methyl] benzyl 2-aminoacetate
  • the title compound was obtained by acid hydrolysing 4- [ (nitrooxy) methyl ] benzyl 2- (tert-butoxycarbonylamino) acetate following procedure described in Intermediate 2 Step B.
  • ARB nitroderivatives to induce vasorelaxation in comparison to native ARBs, was tested in vitro in isolated rabbit thoracic aorta preparations (Wanstall J. C. et al . , Br. J. Pharmacol., 134:463-472, 2001) .
  • Male New Zealand rabbits were anaesthetized with thiopental-Na (50 mg/kg, iv) , sacrificed by exsanguinations and then the thorax was opened and the aorta dissected.
  • Aortic ring preparations (4 mm in length) were set up in physiological salt solution (PSS) at 37°C in small organ chambers (5 ml) .
  • composition of PSS was (mM) : NaCl 130, NaHCO 3 14.9, KH 2 PO 4 1.2, MgSO 4 1.2, HEPES 10, CaCl 2 , ascorbic acid 170 and glucose 1.1 (95% O 2 /5% CO 2 ; pH 7.4) .
  • Each ring was mounted under 2 g passive tension. Isometric tension was recorded with a Grass transducer (Grass FT03) attached to a BIOPAC MP150 System. Preparations were allowed to equilibrate for Ih, and then contracted submaximally with noradrenaline (NA, 1 ⁇ M) and, when the contraction was stable, acetylcholine (ACh, 10 ⁇ M) was added.
  • NA noradrenaline
  • ACh acetylcholine
  • a relaxant response to ACh indicated the presence of a functional endothelium. Vessels that were unable to contract NA or showed no relaxation to Ach were discarded. When a stable precontraction was reached, a cumulative concentration-response curve to either of the vasorelaxant agents was obtained in the presence of a functional endothelium. Each arterial ring was exposed to only one combination of inhibitor and vasorelaxant.
  • Thoracic aorta was obtained from male rabbits. Each animal was sacrificed by exsanguinations under pentobarbital-Na anesthesia and the thoracic aorta was rapidly removed. After removing adhering fat and connecting tissues, the thoracic aorta was cut into 4-5 mm long rings. Each preparation was placed in a 5 ml organ bath containing physiological salt solution (PSS) at the following composition (mM) : NaCl 130.0, KCl 3.7, NaHCO 3 14.9, KH 2 PO 4 1.2, MgSO 4 * 7H 2 O 1.2, Glucose 11.0, HEPES 10.0, CaCl 2 »2H 2 O 1.6.
  • PSS physiological salt solution

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Abstract

L'invention concerne de nouveaux nitrodérivés bloquant les récepteurs de l'angiotensine II, de formule générale (I), et des sels pharmaceutiquement acceptables ou des stéréoisomères correspondants, ainsi que leur utilisation pour le traitement de maladies cardio-vasculaires, rénales et hépatiques chroniques, des processus inflammatoires et des syndromes métaboliques.
PCT/EP2009/051943 2008-02-26 2009-02-19 Nouveaux dérivés bloquant les récepteurs de l'angiotensine ii Ceased WO2009106471A2 (fr)

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US12/866,688 US20110052674A1 (en) 2008-02-26 2009-02-19 Angiotensin ii receptor blocker derivatives
CA2712695A CA2712695A1 (fr) 2008-02-26 2009-02-19 Nouveaux derives bloquant les recepteurs de l'angiotensine ii
JP2010548079A JP2011513269A (ja) 2008-02-26 2009-02-19 新規アンジオテンシンｉｉレセプターブロッカー誘導体
EP09715990A EP2250164A2 (fr) 2008-02-26 2009-02-19 Nouveaux dérivés bloquant les récepteurs de l'angiotensine ii

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Cited By (6)

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WO2010034118A1 (fr) * 2008-09-24 2010-04-01 Oral Delivery Technology Ltd. Composé d’ester d’acide aminé libérant un oxyde nitrique, composition et procédé d’utilisation
WO2011035110A2 (fr) 2009-09-18 2011-03-24 Georgetown University Traitement du stress et/ou de l'hypertension oxydants
CN102757444A (zh) * 2011-04-29 2012-10-31 江苏先声药物研究有限公司 具有一氧化氮供体性质的苯并呋喃类化合物
WO2012152438A1 (fr) * 2011-05-11 2012-11-15 Nicox S.A. Procédé pour la préparation d'ester d'acide de nitrate de composés organiques
US9085508B2 (en) 2008-09-24 2015-07-21 Oral Delivery Technology Ltd. Nitric oxide releasing amino acid ester compound, composition and method of use
CN119591583A (zh) * 2024-12-04 2025-03-11 复旦大学附属中山医院 一种新型沙坦类化合物及其制备方法和应用

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US8207208B2 (en) * 2008-05-15 2012-06-26 Merck Sharp & Dohme Corp. Angiotensin II receptor antagonists
EP2855464B1 (fr) 2012-05-31 2016-10-26 Theravance Biopharma R&D IP, LLC Inhibiteurs de néprilysine donneurs d'oxyde nitrique
US10835615B2 (en) 2015-10-02 2020-11-17 The Johns Hopkins University Supramolecular hydrogels containing angiotensin receptor blockers for targeted treatment of diabetic wounds

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Publication number Priority date Publication date Assignee Title
US5089626A (en) * 1990-08-23 1992-02-18 Merck & Co., Inc. Process for preparing an angiotensin II antagonist
PL1653950T3 (pl) * 2003-07-31 2008-08-29 Nicox Sa Pochodne nitrooksylowe losartanu, walsartanu, kandesartanu, telmisartanu, eprosartanu i olmesartanu jako antagonisty receptorów angiotensyny II do leczenia chorób sercowo-naczyniowych
AU2004270162B2 (en) * 2003-08-28 2010-05-13 Nicox S.A. Nitrosated ad nitrosylated diuretic compouds, compositions and methods of use
CN1984871A (zh) * 2004-07-20 2007-06-20 尼科克斯公司 制备硝基氧基酯、硝基氧基硫酯、硝基氧基碳酸酯和硝基氧基硫代碳酸酯的方法、用于所述方法的中间体及其制备
US20090012057A1 (en) * 2005-02-28 2009-01-08 Nitromed, Inc. Cardiovascular Compounds Comprising Nitric Oxide Enhancing Groups, Compositions and Methods of Use
EP1922069A2 (fr) * 2005-08-08 2008-05-21 Nitromed, Inc. Composes antagonistes de l'angiotensine ii amplifiant l'oxyde nitrique, compositions et methodes d'utilisation associees

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010034118A1 (fr) * 2008-09-24 2010-04-01 Oral Delivery Technology Ltd. Composé d’ester d’acide aminé libérant un oxyde nitrique, composition et procédé d’utilisation
US9085508B2 (en) 2008-09-24 2015-07-21 Oral Delivery Technology Ltd. Nitric oxide releasing amino acid ester compound, composition and method of use
WO2011035110A2 (fr) 2009-09-18 2011-03-24 Georgetown University Traitement du stress et/ou de l'hypertension oxydants
WO2011035110A3 (fr) * 2009-09-18 2011-10-06 Georgetown University Traitement du stress et/ou de l'hypertension oxydants
US9233949B2 (en) 2009-09-18 2016-01-12 Georgetown University Treatment for oxidative stress and/or hypertension
CN102757444A (zh) * 2011-04-29 2012-10-31 江苏先声药物研究有限公司 具有一氧化氮供体性质的苯并呋喃类化合物
CN102757444B (zh) * 2011-04-29 2016-02-10 南京信诺泰医药有限公司 具有一氧化氮供体性质的苯并呋喃类化合物
WO2012152438A1 (fr) * 2011-05-11 2012-11-15 Nicox S.A. Procédé pour la préparation d'ester d'acide de nitrate de composés organiques
CN119591583A (zh) * 2024-12-04 2025-03-11 复旦大学附属中山医院 一种新型沙坦类化合物及其制备方法和应用
CN119591583B (zh) * 2024-12-04 2025-08-22 上海逸芯源生物医药科技有限公司 一种沙坦类化合物及其制备方法和应用

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